Substituted 5-nitro-2-furylamidoximes

ABSTRACT

COMPOUNDS COMPRISING DISUBSTITUTED ACYL AMIDE OXIMES WITH ONE OF THE SUBSTITUENTS BEING 5-NITRO-2-FURYL. THESE COMPOUNDS ARE USEFUL AS ANTIBACTERIAL AND ANTIFUNGAL AGENTS.

United States Patent "ice .Us. Cl. 260247.2 4 Claims ABSTRACT OF THE DISCLOSURE Compounds comprising disubstituted acyl amide oximes with one of the substituents being -nitro-2-furyl. These compounds are useful as antibacterial and antifungal agents.

This application is a continuation-in-part of US. application Ser. No. 640,343, now abandoned, filed May 22, 1967, which is a continuation-in-part of US. application Ser. No. 532,571, filed Mar. 8, 1966, now abandoned, which is a divisional application of US. application Ser. No. 314,849, filed Oct. 9, 1963, now Pat. 3,272,828.

SUMMARY This invention relates to compounds of the formula 0 NH; Rrii 0N= J-R,

In this formula, when R is 5-nitro-2-furyl, R represents hydrogen, loweral'kyl, haloloweralkyl of from 5-17 carbon atoms,

phenyl,

aralkyl,

aryloxyloweralkyl,

lowenalkylaminoloweral kyl,

dialkylaminoloweralkyl,

carboxy,

carboloweralkoxy,

carboloweralkoxyloweralkyl,

carboxamidoloweralkyl,

acylaminoloweralkyl,

halophenyl,

al'koxyphenyl,

hydroxyphenyl,

cyanoloweralkyl,

acylamiuophenyl,

loweral'kylthiophenyl,

nitrophenyl,

aminophenyl,

sulfonamidophenyl,

nitrophenylloweral kyl,

halophenylloweralkyl,

loweralkylphenyl,

diloweralkoxyphenylloweralkyl,

loweralkylhalophenyl,

N-acyl-N-cycloalkylaminoloweralkyl,

Naacyl-N-loweralkylaminoloweralkyl,

N-acyl-N-phenylaminoloweralkyl,

N-acyl-N'-diloweralkylaminoloweralkylaminoloweralkyl,

haloacylaminolowerallcyl,

N,N-dialkyl-N-(arylloweralkyl)-loweralkyl ammonium chloride,

N,N-dialkyl N-(dihaloarylloweralkyl)lower alkyl ammonium chloride,

morpholinoloweralkyl,

piperidinolower alkyl,

3,660,390 Patented May 2, 1972 pyrrolidinoloweralkyl and u-halomethylphenyl; and when R is S-nitro-Z-furyl, R represents haloloweralkyl of 'from 517 carbon atoms, halophenyl, nitrophenylloweralkyl, halophenylloweralkyl, acylaminophenyl, loweralkylphenyl, diloweralkoxyphenylloweralkyl, loweralkylhalophenyl, diloweral'kylaminoloweralkyl, acylaminoloweralkyl, N-acyl-N-cycloalkylaminoloweralkyl, N-acyl-N-loWeralkylaminoloweralkyl, N-acyl-N-phenylaminoloweralkyl, N-acyl-N-diloweralkylaminoloweralkyl, haloacylaminoloweralkyl, acylthioloweralkyl, morpholinoloweralkyl, piperidinoloweralkyl, pyrrolidinoloweralkyl, and a-halomethylphenyl. The terms loweralkyl and loweralkoxy include the straight and branched alkyl and alkoxy radicals containing from one to seventeen carbon atoms, inclusive, except as otherwise indicated. The term cyclo includes rings of from three to seven carbon atoms.

More particularly, the compounds of the present invention have the formulas wherein R in these and succeeding formulas may be any of the previously enumerated radicals, respectively, except 5-nitro-2-furyl.

These novel compounds, and especially those in which R in formula B is haloloweralkyl, are active antibacterial and antifungal agents. For this reason, they can be employed in disinfectant compositions to control a variety of microorganisms such as Salmonella typhimurium, Escherichia coli, Proteus vulgaris, and Alternaria species. In such use, the compounds are dispersed on an inert solid or in a suitable liquid (preferably water) and applied as a dust or spray. In a representative operation, good control of the above-named organisms was obtained when the compound wherein R is chloromethyl in the general formula above was employed in an aqueous medium at a concentration of about 50 parts per million. The new compounds are also effective against Trichomonas vaginalis when applied topically in concentrations of 50 parts per million or less.

DETAILED DESCRIPTION The compounds of the present invention may be prepared by the reaction of equimolar proportions of a 5- nitro-Z-furoyl' halide (preferably the chloride) and a compound of the formula in the presence of an inert solvent such as acetone and a hydrohalide acceptor such aspotassium carbonate. Good results are obtained when the R-substituted amidoxime and hydrohalide acceptor are dissolved in the solvent,

cooled to about -C., and the -nitro-2-furoyl halide also dissolved in the same solvent is added dropwise thereto with rapid stirring. When the addition is complete, stirring is continued at room temperature for several hours. The desired 5-nitro-2-furoylamidoxime which forms is eventually recovered by filtration or concentration, washed with water, dried and recrystallized from a suitable solvent such as acetonitrile or dimethylformamide.

The above method is preferred for compounds of Formula B. The following method may preferably be employed for compounds of Formula C.

General procedure: An amidoxime is condensed with an equimolar quantity of carboxylic acid via an active intermediate resulting from the reaction of the carboxylic acid and an alkylchloroformate in the presence of a mineral acid acceptor such as triethylamine and the like or in the presence of a dialkylcarbodiimide, in anhydrous solvents such as acetone, chloroform, acetonitrile, dimethoxyethane, dimethylformamide and the like, at temperatures ranging from 0-40 over a period of 416 hours. The resulting reaction mixture is filtered and product is obtained by concentration of the filtrates. The residue is purified by crystallization from suitable solvents such as ethyl alcohol or nitromethane.

The following examples are presented to illustrate rather than limit the invention.

EXAMPLE 1 in formula B To 4 grams (0.02 mole) of p-sulfonamidobenzamidoxime melting at 210 C. was added 1.28 grams (0.01 mole) of anhydrous potassium carbonate and 100 ml. of anhydrous acetone. The mixture was cooled to 0 C. and 3.2-6 grams (0.02 mole) of S-nitro-Z-furoyl chloride melting at 40 C. dissolved in ml. of anhydrous acetone was added with stirring over a period of 15 minutes. The mixture was then stirred at room temperature for an additional 7 hours. The solid which formed was removed by filtration, washed successively with water and ethanol and recrystallized from a dimethylformamide-water mixture at 100 C. to obtain the desired product as a crystalline yellow solid melting at 230 C. (seated capillary) with decomposition.

Analysis-Calculated (percent): C, 40.68; H, 2. 84; N, -15.82. Found (percent): C, 40.84; H, 2.86; N, 15.99.

EXAMPLE 2 0-(5-nitro-2-furoyl)-ch1oroacetamidoxime R=ClCH in formula B By substituting chloroacetamidoxime melting at 87 C. for the p-sulfonamidobenzamidoxime of Example 1, the above-named compound was obtained which was found to melt at 165 C.

Analysis.Calculated (percent): C, 33.95; H, 2.44; -N,16.97. Found (percent): C, 34.06; H, 2.46; N, 17.09.

EXAMPLE 3 O- (5-nitro-2-furoyl) -p-nitrobenzamidoxine The reaction of p-nitrobenzamidoxine melting at 169 C. and 5-nitro-2-furoyl chloride in the presence of potassium carbonate and acetone as described in Example 1 produced the desired O-(5-nitro-2-furoyl)-p-nitrobenzamidoxime melting at 198 C.

A nalysis.Calculated (percent): C, 45.01; H, 2.52; N, 17.50. Found (percent): C, 45.07; H, 2.49; N, 17.67.

EXAMPLE 4 O-(5-nitro-2-furoyl)-p-aminobenzamidoxime The reaction of equimolar amounts of 5-nitro-2-furoyl chloride and p-aminobenzamidoxime melting at 171 C. as described in Example 1 resulted in the formation of 4 the desired amidoxime which melted at 235 C. with decomposition.

Analysis.-Calculated (percent): C, 49.66; H, 3.47. Found (percent): C, 50.29; H, 3.52.

EXAMPLE 5 2- (diethylamino-acetamidoxime 0-5-nitro-2-furoate-HC1 R=CH N(C H in Formula B An acetone solution (50 ml.) containing 3.86 g. (0.0264 mole) of 2-diethylamino)-acetamidoxime is chilled. An acetone solution (25 ml.) containing 4.65 g. (0.0264 mole) of 5-nitro-2-furoyl chloride is added with stirring and in the absence of moisture over a period of 5-10 minutes. Cooling is used during the addition. The reaction mixture is stirred at room temperature for 4 hours, the reaction mixture filtered and the residue washed with dry acetone. After drying, 6.71 g. (78.7%) of product, M.P. 134135 dec., is obtained. Crystallization from i-propanol gives material M.P. 123 425.

Analysis.Calculated for C H ClN O (percent): C, 41.19; H, 5.34; N. 17.47. Found (percent): C, 41.46; H, 5.09; N, 17.95.

EXAMPLE 6 N-[ (hydroxyamidino methyl] acetamide 0-5 -nitro-2- furoate O R=CH2NHilCH in Formula 13 To a suspension of 15.0 g. (0.1141 mole) of N-acetylaminoacetamidoxime in 250 ml. of dry acetone is added 9.20 ml. (0.01141 mole) of dry pyridine. A solution of 20.25 g. (0.1141 mole) of 5-nitro-2-furoyl chloride in ml. of dry acetone is added with cooling, rapid stirring, and in the absence of moisture. The product is filtered and washed with air drying 19.28 g. (62.5%), M.P. 179 dec. The product may be crystallized from acetonitrile.

Analysis.Calculated for C H N4O (percent): C, 40.00; H, 3.73; N, 20.74. Found (percent): C, 40.05; H, 3.71; N, 20.55.

EXAMPLE 7 Benzyl[ (hydroxyamidino methyl]dimethylammonium chloride O-5-nitro-2-furoate in formula B To a suspension of 5.0 g. (.02055 mole) of N-benzyl- N,N-dimethylaminoacetamidoxime chloride in 50 ml. of dry acetone is added with stirring and in the absence of moisture a solution of 3.61 g. (0.02055 mole) of 5- nitro-2-furoyl chloride in 25 ml. of acetone. Reaction is allowed to proceed overnight. After filtering the reaction mixture, the residue is washed thoroughly with dry acetone. After drying, 7.33 g. (93.4%) of product, M.P. -166, is obtained. Crystallization from methyl alcohol and benzene raises the melting point to 180 dec.

Analysis.Calcd. for C H ClN O (percent): C, 50.20; H, 5.00; N, 14.64; Cl, 9.26. Found (percent): C, 50.25; H, 5.22; N, 14.62; Cl, 9.08.

EXAMPLES 8-9 1 Using the methods of the foregoing examples, the following compounds of Formula B were made.

In like manner, the reaction of any R-substituted amid- O-(S-nitro-Z-furoyl)-phenoxyacetamidoxime oxime wherein R is as hereinbefore indicated with a O-(-nitro-2-furoyl)carboxyoxalamidoxirne 5-m'tro-2-furoyl halide will evolve hydrohalide of reaction O-(S-nitro-Z-furoyl)-carbomethoxyoxalamidoxime and result in the formation of the corresponding R-sub- O-(S-nitro-Z-furoyl)-fl-carbomethoxypropionamidoxime stituted S-nitro-Z-furoylamidoximes. Representative of 5 O-(S-nitro-Z-furoyl)-o-ch1orobenzamidoxime such compounds considered to be Within the scope of O-(5-nitro-2-furoyl)-p-methoxybenzamidoxime this invention are: O-(5-nitro-2-furoyl)-o-methylthiobenzamidoxime O-(S-nitro-Z-furoyl)-benzamidoxime melting at 170 C. The R-substituted amidoximes employed as one of the 'O- 5-nitro-2-furoyl -formamidoxime O- 5-nitro-2-furoyl -bromoacetamidoxime starting materials are known compounds or can be read O-(5-nitro-2-furoyl)-acetamidoxime metal hydroxide, hydroxylamine hydrochloride and a O-(S-nitro-Z-furoyl)-isobutyramidoxime nitrile of the formula RCEN in an inert solvent such as O-(5-nitro-2-fouroy1)-valeramidoxime ethanol. The solution is then filtered and the filtrate con- O-(S-nitro-Z-furoyl)-2-carboxamidoacetamidoxime centrated to recover the desired amidoxime as a residue O-(S-nitro-Z-furoyl)-N-benzoylaminoacetamidoxime which can be purified by recrystallization from a suitable O- (S-nitro-Z-furoyl) -cyanoaceta1nidoxime solvent. O-(S-nitro-Z-f-uroyl)-phenylacetamidoxime Using methods exemplified in the foregoing examples, O-(5-nitro-2-furoy1)-t-butylaminoacetamidoxime the following compounds, wherein R refers to substitu- O-(S-nitro-Z-furoyl)-diethylaminoacetamidoxime tions in Formula B, were made.

Analysis Calculated Found M.P., M01.

Example R C. Reerystal. solvent 0 H N C H N wt.

12 OCH: 58- 00 (10 51.57 4.32 12.07 51.58 4.24 12.02 349.29

@ 171 Nitromethane 46.66 3.08 16.74 46.85 2. 88 16.90 334.24

14 181482 Acetonltrile 48.31 3.11 12.97 48.30 3.29 13.22 323.70

10 1;. CHz-N(CzH5)2-HC1 123-125 i-Propanol 41.19 5.34 17.47 41.46 5.09 17.95 320.74

20 CHg-N(CH3)7 HC1 157-158 i-Propanol-DMF 36.91 4.48 19.14 37.03 4.52 19.18 292.69

21 CH CH Cl Methanolplusbenzene 50.20 5.00 14.64 50.25 5.22 14.62 382.80

CHrN-CHzCoHs 22 154 DMF-i-propanol 39.47 4.52 16.74 39.94 4.53 16.30 334.72

GET-N H01 23 154 Ethanol 41.45 4.74 17.58 41.30 4.76 17.49 318.72

CH2-N -HC1 24 165 DMF plus diisopropyl ether 43.31 5.15 16. 84 43.29 5.13 16.84 332.74

CHPN H01 25 CHz-N(C3H7-Il)z-HC1 138-139 i-Propanol plus diisopropylethen. 44.77 6.07 16.07 44. 87 6.19 16.30 348.79

183 Methanol 42.54 3.80 12.41 42.69 3.88 12.35 451.70

27 0 188-189 CHBNOZ 50.00 3.04 16.86 50.70 3.65 10.07 '332. 27

TABLEContinued Analysis Calculated Found M.P., Mol. Example R C. Rccrystal. solvent H N C H N wt.

28 178-179 CHgCN 40.00 3. 73 20.74 40.05 3.71 20.55 270.20

CII2NHC 0113 100143 140 i'lropanol 51.13 5.72 15.90 51. 31 5.00 10.12 352. 34

CH2N- 193-195 Methyl 00110501175 42.25 4.20 19.71 42.05 4.10 10.71 284.23

CH:N(CH )CCHa 31 139490 CHgCN 44. 30 4. 73 18.79 44.15 4.94 18.75 298.25

CHzN 0211.) C CH:

32 (a 100-102 l-Iropanol 52.02 4.08 10.13 51.95 4. 29 10.19 340. 29

o1n-N c on.

CHz-N-CCH:

(CH2)2 N(CH3)3 1 Dccomposed.

EXAMPLE 34 EXAMPLES 36-44 Using the methods of the foregoing examples the 5 mm) 2 furamldoxlme O aceturate followmg compounds of Formula C were made.

0 Melting R-omNn om in formula 0 Example R pointf 30 -CH(CH2)aCH1 348.16 104-100 Ten grams (0.0875 mole) of Nacetylglycine is dissolved in 100 ml. of acetone containing 8.86 g. (0.0875

37 -HCH mole) of tnethylarmne. Ma1nta1mng anhydrous cond1t1ons (0 a 432 32 98400 with chilling and stirring, 9.49 g. (0.0875 mole) of ethyl Br chloroformate in 25 m1. of acetone is added dropwi 38 -CH(CH2)13CH7 488.42 100-108 The resulting mixture is stirred for 4 hours and then r filtered to remove the triethylamine hydrochloride. The filtrate is added dropwise with stirring to a solution 39 2)1s 516. 7 98-100 of 15 g. (0.08757) of 5-nitro-2-furylamidoxime in 200 Br ml. of acetone. After addition, the solution is heated at 40 323 69 m 40 overnight with stirring. Chilling and filtering the re-- action mixture gives 11.77 g. (49.7%) of crude products, M.P. 181183 dec. Purification in nitromethane gives a pure product melting at 196-198 dec. weighing 41 309-66 (48.2%). EXAMPLE 35 42 01 344.11 150458 5-nitro-2-furamidoxime O-2(acetylthio)-acetate Q 1 1 :1 R=CH2SCCH3 il1 fo m C 43 C1 3 4 11 1 178479 17.9 g. (0.1045 mole) of 5-nitro-2-furylamidoxime is @411 dissolved in 450 ml. of acetone containing 21.6 g. (0.1045 mole) of N,N-dicyclohexylcarbodiimide. Main- 44 01 344.11 184-135 taining anhydrous conditions and with stirring, a solution of 14 g. (0.1045 mole) of acetylmercapto acetic acid in 50 ml. of acetone is added dropwise. The resulting re- 1 action mixture is allowed to stir overnight at room tem- 7O 01 perature. After removal of N,N-dicyclohexylurea by 111- EL tration, the filtrate is concentrated to yield 33.6 g. of crude product, M.P. -143 dec. Crystallization from ethanol gave 16.95 g. (56.5%) of product, M.P. 162-163 dec.

Analysis Calculated Found Example R MR, 0. Reerystol. solvent 0 H N 0 H N 45..--.. 1 196-198 CHzNOz 40. 00 3. 73 20. 74 39. 87 3. 73 20. 84 270. 20

CHI-NH C CH:

46........'.'...'.."..:...' 1 175-176 CHaNOa 42. 25 4. 26 19. 71 42. 04 4. 36 19. 71 284. 23

' (CHah-NHK") CHa) 47.--.2 r O 1 143145 CHaCN 44. 29 4. 74 18. 78 44. 4. 73 18. 97 298. 26

(CHnh-NHC CH3) 48-..:. 1 141-143 Ethyl acetate- 47. 85 5. 56 17. 17 47. 65 5. 55 17. 34 326. 31

(CH2) sNH( I CH 49 1 167-169 Ethanol 35. 48 2. 97 18. 39 35. 48 2. 98 18. 304. 65

CH1-NHC 0 11201 50 1 167-168 CHaCN i-propanol---.-.'. 42. 4. 26 19. 71 42.04 4. 34 19. 92 284. 23

CHa-N(CH:) (3 CH:

51 O 1 172-173 CHsCN 42. 25 4. 26 19. 71 41. 92 4. 29 19. 60 284. 23

OHz-NHP) CHzCHa 52 -:...r.-'... O 1 183-184 CHaCN 50. 48 3. 87 16. 83 50. 46 3. 89 16. 89 333. 09

CHzNHiJQ 53--.: 0 1 167-469 CHaCN 42. 25 4. 26 19. 71 42. 00 4. 37 19. 50 284. 23

CHNH CH3 (5H.

54 O 1 162-163 Ethanol "1.1.2.1--.- 37. 63 3. 16 14. 63 37. 36 3. 12 14. 56 287. 25

(3112- S 3 CH3 1 Decomposed.

MINIMUM INHIBITORY CONCENTRATION, COMPOUNDS OF FORMULA B Microorganism Compound (in p.p.m.) Staph. Tnch. Proteus of Example aureaus vaginalis vulaans Alternana MINIMUM INHIBITORY CONCENTRATION, COMPOUNDS OF FORMULA C Microorganism Trich.

Compound of Example Staph. aureaus vaamalis Proteus vulgarzs Additionally, the compound of Example 46 has been found to have good activity against Trichomonas vaginalis in mice. When administered orally at a dosage level of 500 mg./kg., 50 percent of the parasites were killed. At a dosage level of 750 mg./kg., administered orally, from 60-78 percent of the parasites were killed. The LD when administered intraperitoneally was found to be 750 rug/kg. When administered orally to mice at the LD level, no deaths occurred. The compound of Example 48 was likewise found to have activity against Trichomonas vaginalis in mice. When administered orally at a dosage level of 500 mg./kg., from 56 to 78 percent of the parasites were killed, the LD for oral administration being 750 mg./kg.

What is claimed is:

1. A compound of the formula:

wherein R is a member of the group consisting of hydrogen, loweralkyl, chloromethyl, bromomethyl, phenyl, phenylalkyl, phenoxyloweralkyl, loweralkylalaminoloweralkyl, dialkylaminoloweralkyl, carboxy, carboloweralkoxy, carboloweralkoxyloweralkyl, carboxamidoloweralkyl, acylaminoloweralkyl, halophenyl, alkoxyphenyl, hydroxyphenyl, cyanoloweralkyl, acylaminophenyl, loweralkylthiophenyl, nitrophenyl, aminophenyl, sulfonamidophenyl, nitrophenylloweralkyl, halophenylloweralkyl, Ioweralkylphenyl, diloweralkoxyphenylloweralkyl, lower: alkylhalophenyl, N-acyl-N-cycolalkyamiuoloweralkyl, N- acyl N loweralkylaminoloweralkyl, N-acyl-N-phenylaminoloweralkyl, N-acy1-N-diloweralkylaminoloweralkylaminoloweralkyl, haloacylaminoloweralkyl, N,N-dialkyl- N-(phenylloweralkyl)-loweralkyl, ammonium chloride, N,N-dialkyl-N-(dihalophenylloweralkyl), loweralkyl ammonium chloride, morpholinoloweralkyl, piperidinoloweralkyl, pyrrolidinoloweralkyl, and wherein acyl is a member of the group consisting of the benzoyl and acetyl radicals and wherein both loweralkyl and alkyl are limited to 1 to 5 carbon atoms.

2. A compound as claimed in claim 1 wherein R is a member of the group consisting of N-acetyl-N-methylaminomethyl and N-acylaminoloweralkyl.

3. A compound as claimed in claim 1 wherein R is a member of the group consisting of chloromethyl, bromomethyl, p-sulfonamidophenyl, phenyl, p-aminophenyl, nitrophenyl, N,N-dimethyl-N-benzylmethylammonium, pmethoxyphenyl, p-chlorophenylmethyl, dimethylaminomethyl, morpholinomethyl, N-acetyl, N-cyclohexylaminomethyl, and N-acetylaminomethyl.

4. A method for the preparation of a compound of the formula:

wherein R is a member of the group consisting of hydrogen, loweralkyl, chloromethyl, bromomethyl, phenyl, phenylalkyl, phenoxyloweralkyl, loweralkylaminoloweralkyl, dialkylaminoloweralkyl, carboxy, carboloweralkoxy, carboloweralkoxyloweralkyl, carboxamidoloweralkyl, acylaminoloweralkyl, halophenyl, alkoxyphenyl, hydroxyphenyl, cyanoloweralkyl, acylaminophenyl, loweralkylthiophenyl, nitrophenyl, aminophenyl, sulfonamidophenyl, nitrophenylloweralkyl, halophenylloweralkyl, loweralkylphenyl, diloweralkoxyphenylloweralkyl, loweralkylhalophenyl, N-acyl-N-cycloalkylaminoloweralkyl, N-

acyl N loweralkylaminoloweralkyl, N-acyl-N-phenylaminoloweralkyl, N-acyl-N'-diloweralkylaminoloweralkylaminoloweralkyl, haloacylaminoloweralkyl, N,N-dialkyl- N-(phenylloweralkyl)-lowera1kyl ammonium chloride, N, N dialkyl N (dihalophenylloweralkyl) loweralkyl ammonium chloride, morpholinoloweralkyl, 'pi'peridinoloweralkyl, pyrrolidinoloweralkyl, and wherein acyl is a member of the group consisting of the benzoyl and acetyl radicals and wherein both loweralkyl and alkyl are limited to 1 to 5 carbon atoms; which comprises: reacting a carboxylic acid with a reactant comprising an admixture of an alkylchloroformate and a mineral acid acceptor to produce an active intermediate; condensing an amidoxime with said active intermediate; and recovering the product formed.

References Cited UNITED STATES PATENTS 3,272,833 9/1966 Von Esch et al 260347.3

ALEX MAZEL, Primary Examiner B. DENTZ, Assistant Examiner US. Cl. X.R. 

